Process for preparing 3-heteroaryl-3-hydroxypropanoic acid derivatives

ABSTRACT

The invention relates to a process for preparing enantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid derivatives and 3-heteroaryl-1-aminopropan-3-ols, and to their use.

This application is a divisional of U.S. Ser. No. 10/669,424, which ispending and claims foreign priority benefit under 35 U.S.C. §119 of theGerman Patent Application No. 102 44 811.6 filed Sep. 26, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a process for preparing enantiomer-enriched3-heteroaryl-3-hydroxypropanoic acid derivatives and3-heteroaryl-1-aminopropan-3-ols, and to their use.

2. Description of Related Art

3-Heteroaryl-3-hydroxypropanoic acid derivatives and3-heteroaryl-1-aminopropan-3-ols have gained industrial significance, inparticular, as intermediates for producing medicaments. Thus, some3-heteroaryl-3-hydroxypropanoic acid derivatives and3-heteroaryl-1-aminopropan-3-ols are used, for example, as precursorsubstances for preparing inhibitors of the uptake of serotonin ornoradrenaline. In the case of some of these inhibitors, it has beenshown that certain enantiomers are not only inactive, or less active,but are even able to exhibit undesirable side-effects (U.S. Pat. No.5,104,899).

A process for preparing enantiomer-enriched(1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol proceeding from1-(2-thiophenyl)-3-chloropropan-1-one is described in Chirality 2000,12, 26-29. Following reduction to the racemic3-chloro-1-(2-thienyl)-1-propanol, the racemate is resolved enzymicallyand the (S) enantiomer is subjected to further reaction with NaI andmethylamine to give (S)-3-(methylamino)-1-(2-thiophenyl)propan-1-ol.This method suffers from the disadvantage that, in principle, only 50%of the desired enantiomer can be obtained when racemates are resolvedenzymically and the total yield is therefore economically unacceptable.

It is already known that microorganisms, such as yeasts or fungi, can beused to reduce 3-oxocarboxylic acid derivatives enantioselectively togive the corresponding enantiomer-enriched 3-hydroxycarboxylic acidderivatives (see also Sybesma et al., Biocatalysis andBiotransformation, 1998, Vol. 16, 95-134; Dahl et al., Tetrahedron:Asymmetry 10, 1999, 551-559, Dehli et al., Tetrahedron: Asymmetry 11,2000, 3693-3700, Hayakawa et al, Tetrahedron Letters, 1998, Vol. 39,67-70, Cabon et al., Tetrahedron: Asymmetry 6, 1995, 2199-2210 andSmallridge et al., Tetrahedron Letters, 1998, Vol. 39, 5121-5124).

In addition, EP-A 447 938 describes the enantioselective synthesis of2-halo-3-hydroxy-3-phenylpropanoic esters by using various organisms toreduce the 2-halo-3-oxo-3-phenylpropanoic esters.

Furthermore, Chenevert et al., Tetrahedron 1992, Vol. 48, 6769-6776disclose the asymmetric synthesis of both enantiomers of theantidepressant fluoxetine(N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylaminehydrochloride). An important step in the multi-stage synthesis is thatof using microorganisms to effect the enantioselective reduction of theethyl 3-oxo-3-phenylpropanoate.

An analogous synthesis, for preparing (R)-tomoxetine, which acts as anantidepressant, is described in Kumar A. et al., Tetrahedron Letters,1991, Vol. 32, 1901-1904. The enantioselective reduction of the ethyl3-oxo-3-phenylpropanoate to give ethyl 3-hydroxy-3-phenylpropanoate isan important step in this synthesis as well.

However, the enantioselective reduction of heteroaryl ketones has notpreviously been described.

There was still the need, therefore, to provide a process which makes itpossible to prepare enantiomer-enriched 3-heteroaryl-3-hydroxypropanoicacid derivatives.

SUMMARY OF THE INVENTION

A process for preparing stereoisomer-enriched3-heteroaryl-3-hydroxypropanoic acid derivatives has now been found,which process is characterized in that

-   -   compounds of the formula (I)        heteroaryl-CO—CH₂W   (I)    -   in which    -   heteroaryl is a monocyclic or bicyclic aromatic radical having a        total of from 5 to 10 ring atoms, where none, one or two ring        atoms, selected from the group oxygen, sulphur and nitrogen, can        be present per cycle and one or two can be present in the entire        aromatic radical, and where the monocyclic or bicyclic aromatic        radical is optionally substituted, once, twice or three times,        by radicals which are selected, in each case independently of        each other, from the group hydroxyl, C₁-C₈-alkyl, cyano, COOH,        COOM, where M is an alkali metal ion or a half equivalent of an        alkaline earth metal ion, COO—(C₁-C₄-alkyl), O—(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)₂, NH—(C₁-C₄-alkyl), fluorine, NO₂, chlorine,        bromine, C₁-C₄-fluoroalkyl, CONH₂ or CONH—(C₁-C₄-alkyl), and    -   W is C(O)YR¹ _(n), where Y is=oxygen and n is=1 or Y is nitrogen        and n is=2, or    -   W is CN, and    -   R¹ are, in each case independently of each other, hydrogen,        C₁-C₈-alkyl, C₄-C₁₀-aryl or C₅-C₁₁-arylalkyl or, when Y is        nitrogen, the two radicals R¹ are together C₃-C₅ alkylene,        -   are reacted in the presence of microorganisms and/or cell            preparations thereof, and        -   in the presence of water having a pH range of from 3 to 11,            based on 25° C.,            and, in this way, enantiomer-enriched compounds of the            formula (II),            heteroaryl-CH(OH)—CH₂W   (II)            in which heteroaryl and W have the abovementioned meaning,            are obtained.

DETAILED DESCRIPTION OF THE INVENTION

Within the context of the invention, all the radical definitions,parameters and specifications which are general or which are mentionedin preference ranges, and which are given above or cited in that whichfollows, can be combined amongst themselves, that is between therespective ranges and preference ranges as well, in any arbitrarymanner.

Within the meaning of the invention, the term enantiomer-enrichedencompasses, in particular, enantiomerically pure compounds or arbitrarymixtures of enantiomers in which one enantiomer is present in a largerproportion than the other enantiomer, preferably in a relativeproportion of from 60% to 100 mol %, particularly preferably from 80 to100 mol % and, very particularly preferably, from 90 to 100 mol %.

Within the context of the invention, alkyl is, in each caseindependently, a straight-chain or cyclic, independently thereofbranched or unbranched, alkyl radical which can be further substitutedby C₁-C₄-alkoxy radicals. The same applies to the nonaromatic moiety ofan arylalkyl radical.

For example, within the context of the invention, C₁-C₄-alkyl is methyl,ethyl, 2-ethoxyethyl, n-propyl, isopropyl, n-butyl and tert-butyl, whileC₁-C₈-alkyl is, in addition to this, for example, n-pentyl, cyclohexyl,n-hexyl, n-heptyl, n-octyl or iso-octyl.

Fluoroalkyl is, in each case independently, a straight-chain, cyclic,branched or unbranched alkyl radical which is substituted, once, morethan once or completely, by fluorine atoms.

For example, C₁-C₄-fluoroalkyl is trifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, nonafluorobutyl and heptafluoroisopropyl.

Within the context of the invention, aryl is, for example andpreferably, carbocyclic aromatic radicals or heteroaromatic radicalswhich contain no, one or two, but at least one in the entireheteroaromatic radical, heteroatom(s) which is/are selected from thegroup nitrogen, sulphur and oxygen.

In addition, the carbocyclic aromatic radicals or heteroaromaticradicals can be substituted by one or two substituents per cycle, whichsubstituents are selected, in each case independently of each other, forexample and preferably, from the group hydroxyl, C₁-C₄-alkyl, cyano,COOH, COOM, where M is an alkali metal ion or a half equivalent of analkaline earth metal ion, COO—(C₁-C₄-alkyl), O—(C₁-C₄-alkyl),N(C₁-C₄-alkyl)₂, NH—(C₁-C₄-alkyl), fluorine, chlorine, bromine,C₁-C₄-fluoroalkyl, CONH₂ or CONH—(C₁-C₄-alkyl). The same applies to thearyl moiety of an arylalkyl radical.

In the formulae (I) and (II), heteroaryl is preferably a monocyclicaromatic radical having a total of 5 or 6 ring atoms in which one or tworing atoms are selected from the group oxygen, sulphur and nitrogen andwhere the monocyclic aromatic radical contains no, one or two radical(s)which is/are selected, in each case independently of each other, fromthe group methyl, ethyl, n-propyl, isopropyl, cyano, COOH, COONa, COOK,COO-methyl, COO-ethyl, COO-tert-butyl, COO-phenyl, methoxy, ethoxy,dimethylamino, diethylamino, methylamino, ethylamino, fluorine,chlorine, NO₂, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl,CONH₂ and CONH-methyl.

Heteroaryl is, particularly preferably, 2- or 3-thiophenyl, 2- or3-furanyl, 2- or 3-pyrrolyl, 3- or 4-pyrazolyl, 1-, 2- or 4-thiazolyl,1-, 2- or 4-oxazolyl, 2-, 4- or 5-imidazolyl, 2-, 3- or 4-pyridyl, 2- or3-pyrazinyl, 2-, 4- or 5-pyrimidyl, 3-, 4-, 5- or 6-pyridazinyl, 2- or3-indolyl, 3-indazolyl, indazolyl, 2- or 3-benzofuranyl, 2- or3-benzothiophenyl, 2-, 3- or 4-quinolinyl or isoquinolinyl, where eachof the radicals mentioned carries no, one or two, and preferably no,substituents which are in each case selected, independently of eachother, from the group methyl, ethyl, n-propyl, isopropyl, cyano,methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, pentafluoroethyland heptafluoroisopropyl.

Heteroaryl is very particularly preferably 2-thiophenyl.

R¹ is preferably CN or COOR¹, where R¹ is hydrogen or methyl or ethyl.

Preferred compounds of the formula (I) are methyl3-oxo-3-(2-thiophenyl)propanoate, ethyl3-oxo-3-(2-thiophenyl)propanoate, methyl3-oxo-3-(3-thiophenyl)propanoate, ethyl3-oxo-3-(3-thiophenyl)propanoate, methyl 3-oxo-3-(2-furanyl)propanoate,ethyl 3-oxo-3-(2-furanyl)propanoate, methyl3-oxo-3-(3-furanyl)propanoate, ethyl 3-oxo-3-(3-furanyl)propanoate,methyl 3-oxo-3-(2-pyridinyl)propanoate, ethyl3-oxo-3-(2-pyridinyl)propanoate, methyl 3-oxo-3-(3-pyridinyl)propanoate,ethyl 3-oxo-3-(3-pyridinyl)propanoate, methyl3-oxo-3-(4-pyridinyl)propanoate, ethyl 3-oxo-3-(4-pyridinyl)propanoate,3-oxo-3-(2-thiophenyl)propanonitrile,3-oxo-3-(3-thiophenyl)propanonitrile, 3-oxo-3-(2-furanyl)propanonitrile,3-oxo-3-(3-furanyl)propanonitrile, 3-oxo-3-(2-pyridinyl)propanonitrile,3-oxo-3-(3-pyridinyl)propanonitrile, 3-oxo-3-(4-pyridinyl)propanonitrileand N-(methyl)-3-oxo-3-(2-thiophenyl)propanamide.

The microorganisms which are preferably employed are bacteria, yeasts orfungi, with both wild types and transformed strains being included.

Microorganisms which are particularly preferred are yeasts and fungi,very particularly preferably those of the genera Saccharomyces,Geotrichum, Candida, Pichia, Hansenula, Yarrowia, Rhizopus, Mortierella,Mucor, Sporotrichum, Rhodotorula, Trichoderma, Aspergillus, Penicillium,Pullaria, Cunninghamella and Curvularia.

Microorganisms which are even more preferred are Saccharomycescereviseae and Geotrichum candidum.

Cell preparations are to be understood as meaning: purified orunpurified lysed cells which can be used either in the moist state or inthe dried state, for example as lyophilisates.

Preference is given to using microorganisms.

In a preferred embodiment, the microorganisms are grown, prior to thecompounds of the formula (I) being reacted, on complex or mineralnutrient media, using culturing methods which are customary per se forgrowing the given microorganisms, such as culturing in shaken flasks,batch fermentations, fed-batch fermentations or continuousfermentations, up to an optical density of from 1 to 800, preferably offrom 5 to 300, measured at a wavelength of 600 nm (OD₆₀₀), andconcentrated, where appropriate, after having been grown.

The microorganisms can be grown, for example, at temperatures of between10 and 60° C., preferably of between 20 and 40° C.

In addition, the pH when growing the microorganisms can, for example, bebetween pH 3 and pH 9, preferably between pH 4 and pH 8, particularlypreferably between pH 5 and pH 7.5. In this connection, pH values are ineach case based on 25° C., within the entire scope of the invention.

The microorganisms can be grown under aerobic or anaerobic conditions;they are preferably grown aerobically.

For the reaction, the compound of the formula (I) is, in a preferredembodiment, added to the microorganisms which are either present in thegrowth medium or resuspended, where appropriate after priorsedimentation, in an isotonic solution.

In this connection, the isotonic solution can be a mineral salt solutionor also a nutrient medium for microorganisms.

The mixture can, for example and preferably, be shaken or stirred and,where appropriate, aerated.

The process according to the invention can be carried out in a pH rangeof from pH 3 to pH 11, preferably of from pH 4 to pH 10, andparticularly preferably of from pH 6 to pH 8.

The process according to the invention is, furthermore, customarilycarried out at a temperature of from 10 to 60° C., preferably of from 18to 45° C.

The duration of the reaction can be from 10 min to 96 hours, preferablyfrom 60 min to 72 hours and particularly preferably from 2 to 48 hours.

The process according to the invention can be carried out such that thecompounds of the formula (I) are added once, several times orcontinuously.

The sum of the concentrations of the compounds of the formulae (I) and(II) in the cell suspension can be between 1 and 900 mM, preferablybetween 2 and 500 mM, particularly preferably between 3 and 250 mM.

In order to increase the solubility of the starting compound in thereaction medium, it is possible, in a preferred embodiment, to addauxiliary substances such as polar, water-miscible solvents, such asglycerol, dimethylformamide or dimethyl sulphoxide, or other auxiliarysubstances, such as cyclodextrins.

In addition, the process according to the invention can be carried outin the presence of an organic solvent, for example in a multiphasesystem such as, in particular, a two-phase system.

Organic solvents which are suitable for this purpose are, for example,organic solvents which are not miscible with water or which are misciblewith at most 10% by volume, such as aliphatic or aromatic, whereappropriate chlorinated, solvents, such as petroleum ether, hexane,octane, heptane, toluene, the isomeric xylenes, chlorobenzene,dichloromethane and silicone oils. Frequently, the starting compound canalso itself be used as the organic phase.

The compounds of the formula (II) can be isolated in a manner known perse, for example by extracting with an organic solvent, or isolated, if amultiphase system was used, by means of separating off the organic phaseand, where appropriate, further extraction and subsequent removal of theorganic solvent.

Preference is given to using, for this purpose, solvents such astoluene, ethyl acetate, dichloromethane, isobutyl ketone, cyclohexaneand methylcyclohexane, preferably ethyl acetate. The extraction can inthis case be effected by either continuously or discontinuouslysupplying the extracting agent. In the simplest case, the purificationis effected by extracting, while shaking, with the previously mentionedextracting agents.

If desired, a further purification can be effected by means ofdistillation or, in the case of compounds of the formula (I) which aresolid at room temperature, by means of recrystallization.

If the process according to the invention is carried out in a multiphasesystem, the product can also be isolated directly by subjecting theorganic phase to fractional distillation.

In a manner according to the invention, the enantiomer-enrichedcompounds of the formula (II) are obtained, with the stereogenic carbonatom which carries the heteroaryl group and the hydroxyl group usuallyexhibiting the (S) configuration.

The process according to the invention is particularly suitable forpreparing methyl(S)-3-hydroxy-3-(2-thiophenyl)propanoate,ethyl(S)-3-hydroxy-3-(2-thiophenyl)propanoate,methyl(S)-3-hydroxy-3-(3-thiophenyl)propanoate,ethyl(S)-3-hydroxy-3-(3-thiophenyl)propanoate,methyl(S)-3-hydroxy-3-(2-furanyl)propanoate,ethyl(S)-3-hydroxy-3-(2-furanyl)propanoate,methyl(S)-3-hydroxy-3-(3-furanyl)propanoate,ethyl(S)-3-hydroxy-3-(3-furanyl)propanoate,methyl(S)-3-hydroxy-3-(2-pyridinyl)propanoate,ethyl(S)-3-hydroxy-3-(2-pyridinyl)propanoate,methyl(S)-3-hydroxy-3-(3-pyridinyl)propanoate,ethyl(S)-3-hydroxy-3-(3-pyridinyl)propanoate,methyl(S)-3-hydroxy-3-(4-pyridinyl)propanoate,ethyl(S)-3-hydroxy-3-(4-pyridinyl)propanoate,(S)-3-hydroxy-3-(2-thiophenyl)propanonitrile,(S)-3-hydroxy-3-(3-thiophenyl)propanonitrile,(S)-3-hydroxy-3-(2-furanyl)propanonitrile,(S)-3-hydroxy-3-(3-furanyl)propanonitrile,(S)-3-hydroxy-3-(2-pyridinyl)propanonitrile,(S)-3-hydroxy-3-(3-pyridinyl)propanonitrile,(S)-3-hydroxy-3-(4-pyridinyl)propanonitrile andN-(methyl)-(S)-3-hydroxy-3-(2-thiophenyl)propanamide.

The process according to the invention is furthermore suitable, inparticular, as step a) in a process for preparing enantiomer-enrichedcompounds of the formula (VI),heteroaryl-CH(OH)—CH₂—CH₂—NR²R³   (VI)

-   -   in which    -   heteroaryl has the same meaning as that given under formula (I),        and    -   R² and R³ are, in each case independently of each other,        hydrogen, C₁-C₈-alkyl, C₄-C₁₄-aryl or C₅-C₁₅-arylalkyl, or the        two radicals R² and R³ are together C₃-C₁₂-alkylene, which is        characterized in that    -   in a step a),        -   compounds of the formula (I) are converted, as previously            described, into enantiomer-enriched compounds of formula            (II)            heteroaryl-CH(OH)—CH₂—CO—CH₂W   (II)        -   where, in each case,        -   heteroaryl and W have the meanings mentioned under formula            (I), and    -   in a step b)        -   i) when W is COOR¹ and R¹ is hydrogen, C₁-C₈-alkyl,            C₄-C₁₀-aryl or C₅-C₁₁-arylalkyl,            -   the enantiomer-enriched compounds of formula (II) are                reacted with amines of the formula (III)                HNR²R³   (III)            -   in which R² and R³ have the meaning mentioned under                formula (VI), to give enantiomer-enriched compounds of                the formula (IV)                heteroaryl-CH(OH)—CH₂—CO—NR²R³   (IV)            -   in which heteroaryl, R² and R³ have the previously                mentioned meanings, or        -   ii) when W is CON(R¹)₂ and the R¹ radicals are in each case,            independently of each other, hydrogen, C₁-C₈-alkyl,            C₄-C₁₀-aryl or C₅-C₁₁-arylalkyl, or the two R¹ radicals are            together C₃-C₅-alkylene,            -   the enantiomer-enriched compounds of the formula (II)                are converted, where appropriate by reacting with amines                of the formula (III), into enantiomer-enriched compounds                of the formula (IV), and        -   iii) when W is CN, the compounds of the formula (II) are            converted directly, by means of aminolysis/hydrolysis, into            compounds of the formula (IV), or are initially converted,            by means of hydrolysis, partial hydrolysis or mixed            alcoholysis/hydrolysis, into compounds of the formula (V)            heteroaryl-CH(OH)—CH₂—CO—R⁴   (V)            -   in which heteroaryl has the meaning given under formula                (I)            -   and R⁴ is OR¹ or NH₂, where R¹ has the abovementioned                meaning, and            -   are then converted, by amidation in analogy with i) or,                where appropriate, in analogy with ii), into                enantiomer-enriched compounds of the formula (IV)    -   in a step c),        -   the enantiomer-enriched compounds of the formula (IV) are            converted, by means of reduction, into enantiomer-enriched            compounds of the formula (VI) having the abovementioned            meaning.

In the formulae (III), (IV) and (VI), R² and R³ are particularlypreferably, in each case independently, hydrogen, methyl, ethyl,isopropyl, phenyl or benzyl.

In the formulae (III), (IV) and (VI), NR¹R² is, in its entirety,particularly preferably methylamino, ethylamino and isopropylamino.

In the formulae (III), (IV) and (VI), NR¹R² is, in its entirety, veryparticularly preferably methylamino.

The compounds of the formula (I) which can be used for the processaccording to the invention comprising steps a), b) and c) are eitherknown from the literature or can be prepared in analogy with theliterature.

Compounds of the formula (I) in which W is not CN are preferablyobtained by reacting compounds of formula (VII)heteroaryl-CO—CH₃   (VII)in which heteroaryl has the meaning and preference ranges mentionedunder formula (I), with compounds of the formula (VIII),R¹—O—W   (VIII)

-   -   in which    -   R¹ and W have the same meanings as those which were given under        the formula (I), with W not being CN, in the presence of a base.

The reaction of 2-acetylthiophene with dimethyl carbonate, diethylcarbonate, diphenyl carbonate or dibenzyl carbonate, methyl N-methylcarbamate, ethyl N-methyl carbamate, methyl N,N-dimethyl carbamate orethyl N,N-dimethyl carbamate may be mentioned by way of example.

Such a reaction is described, for example, in Tetrahedron Lett. 1998,39, 4995 and can be applied in an analogous manner, for example, for thereaction of 2-acetylthiophene with methyl N-methyl carbamate or ethylN-methyl carbamate to give N-(methyl)-3-oxo-3-(2-thiophenyl)propanamide.

It is furthermore also possible to obtain compounds of the formula (Ia)heteroaryl-CH(OH)—CH₂—CO—NHR²   (Ia)by reacting compounds of the formula (VII) with compounds of the formula(IX)R²—NCO   (IX)in the presence of a base.

In step b) of the process according to the invention, theenantiomer-enriched compounds of the formula (II) are converted in amanner known per se, in accordance with i), ii) or iii), intoenantiomer-enriched compounds of the formula (IV).

Houben Weyl “Methoden der Organischen Chemie [Methods of organicchemistry]”, 4th edition, volume E 5, 941-1010 provides a review of thepreparation of carboxamides from carboxylic acids, carboxylic esters orother carboxamides.

If liquid or gaseous amines of the formula (III) are employed at roomtemperature, preference is then given to using solutions of the amines.For example, in the case of methylamine, it is possible toadvantageously use solutions consisting of methylamine in water,methanol or ethanol for reacting compounds of the formula (II) in whichW is COOR¹. Reactions of amines of the formula (III) in the presence ofcoupling reagents such as 2-halopyridinium or 2-halo-1,3-thiazoliumsalts, or in the presence of acid cation exchangers, are suitable, forexample, for converting free carboxylic acids of the formula (II) intothe amides of the formula (IV).

According to step b), enantiomer-enriched compounds of the formula (IV)are then obtained from enantiomer-enriched compounds of the formula(II).

The compounds of the formula (IV) can then be reduced to give thecompounds of the formula (VI). The reduction of carboxamides to give thecorresponding amines is known in principle and is presented in summaryin Houben Weyl “Methoden der Organischen Chemie”, 4th edition, volume E16 d, 987-1003.

Preference is given to reacting compounds of the formula (VI) withcomplex boron hydrides or aluminium hydrides, such as lithium aluminiumhydride, Red-Al® (sodium bis(2-methoxyethoxy)dihydroaluminate) or sodiumborohydride.

Particular preference is given to reacting compounds of the formula (VI)with lithium aluminium hydride.

The reductions are preferably carried out at temperatures in the rangefrom room temperature to 150° C., particularly preferably in the rangefrom 50 to 110° C. While the reductions are usually carried out inethers as solvents, preferably in cyclic ethers such as tetrahydrofuranor dioxane, reactions using Red-Al® can also be carried out in tolueneas the solvent.

The enantiomer-enriched compounds of the formula (VI) are obtained in amanner according to the invention.

The following may be mentioned as being preferred compounds of theformula (VI):

(1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol,(1R)-3-(methylamino)-1-(2-thio-phenyl)-1-propanol,(1S)-3-(dimethylamino)-1-(2-thiophenyl)-1-propanol and(1R)-3-(dimethylamino)-1-(2-thiophenyl)-1-propanol, with(1S)-3-(methylamino)-1-(2-thiophenyl)-1-propanol being even morepreferred.

The enantiomer-enriched compounds of the formula (VI) which can beprepared in accordance with the invention are particularly suitable forpreparing enantiomer-enriched compounds of the formula (X)heteroaryl-CH(OR⁶)—CH₂—CH₂NR²R³   (X)

-   -   in which    -   heteroaryl, R² and R³ have the meanings and preference regions        given under formula (I), and    -   R⁶ is phenyl or naphthyl which can be substituted, not at all,        once or more than once, by substituents which are selected, in        each case independently of each other, from the group cyano,        CO—(C₁-C₁₂-alkyl), O—(C₁-C₁₂-alkyl), (C₁-C₁₂-alkyl), fluorine,        chlorine, bromine or C₁-C₁₂-fluoroalkyl.    -   R⁶ is preferably naphthyl.

Preferred compounds of the formula (X) are

(S)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine and(R)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine and theirammonium salts.

The invention therefore also encompasses a process which

-   -   as step d),    -   encompasses the reaction of enantiomer-enriched compounds of the        formula (VI) with compounds of the formula (XI) to give        enantiomer-enriched compounds of the formula (X) in the presence        of a base.

In formula (XI),R⁶-Hal   (XI)

-   -   R⁶ has the meaning mentioned under the formula (X), and    -   Hal is fluorine, chlorine, bromine or iodine, preferably        fluorine.

1-Fluoronaphthalene and 4-chlorobenzotrifluoride are preferably used ascompounds of the formula (XI).

The bases which can be used are those which are able to at leastpartially deprotonate the compounds of the formula (VI) at the alcoholfunction.

These bases include, for example, alkaline earth metal or alkali metalhydrides, hydroxides, amides, alcoholates or carbonates, such as sodiumhydride, sodium amide, lithium diethylamide, sodium methoxide, sodiumethoxide, potassium tert-butoxide, sodium hydroxide and potassiumhydroxide.

The compounds which can be prepared in accordance with the invention areparticularly suitable for use as active compounds in medicaments suchas, in particular, inhibitors of serotonin or noradrenaline uptake, oras intermediates thereof.

The process according to the invention enjoys the advantage that it ispossible to use readily available starting compounds to synthesizeenantiomer-enriched 3-heteroaryl-3-hydroxypropanoic acid derivatives and3-heteroaryl-1-aminopropan-3-ols, and their secondary products, on anindustrial scale in high overall yields, high enantiomer excesses andhigh purities.

EXAMPLES Examples 1 and 2 Reduction of methyl3-oxo-(2-thiophenyl)propanoate Using Different Strains of the Baker'sYeast Saccharomyces cereviseae

The yeast strains (Saccharomyces cereviseae NG 247, Uniferm GmbH & CoKG, Monheim; Saccharomyces cereviseae Y278, Deutsche Hefe Werke [GermanYeast Works] GmbH & Co oHG, Hamburg) were grown overnight, at 28° C. andwith shaking (200 rpm), in 100 ml Erlenmeyer flasks containing 25 ml ofYM medium (yeast extract, 3.0 g/l; malt extract, 3.0 g/l; peptone, 5.0g/l; glucose, 10.0 g/l).

Each of the two yeast strains was incubated, at 28° C. and while shaking(200 rpm), in three 1-litre Erlenmeyer flasks which contained 200 ml ofYM medium which had previously been inoculated with 12 ml of preliminaryculture. Growth was monitored by measuring the optical density at 600 nm(OD₆₀₀). After 6-7 h, the cultures reached an OD₆₀₀ of 3 and wereharvested by centrifugation (15 min, 8 000×g) and stored overnight at 4°C. in a refrigerator. For the reaction, 250 μl of 1 M potassiumphosphate buffer (pH 7) and 250 μl of 1M methyl3-oxo-(2-thiophenyl)propanoate were added to 5 ml of the cell pellet andthe whole was shaken in screw cap 13 ml glass tubes. 300 μl of thereaction mixture were removed at regular intervals and extracted with300 μl of ethyl acetate or toluene. After the subsequent centrifugation(5 min, 5000×g) for separating the phases, the organic phase wasanalysed by chiral gas chromatography. The results are recorded inTab. 1. TABLE 1 Reduction of methyl 3-oxo-(2-thiophenyl)propanoate usingdifferent yeast strains. [c] of starting Reaction Example Yeast straincompound time [h] Product Yield ee (S) 1 NG 247 50 mM 24

75% >97% 2 Y278 50 mM 24

77% >97%

Example 3 Reduction of 3-(2-thiophenyl)-3-oxopropano-1-nitrile UsingSaccharomyces cereviseae Y278

The yeast cells were grown, and the reaction was carried out, asdescribed in Examples 1 and 2. The result is recorded in Table 2. TABLE2 Starting Reaction Yield of Example Yeast strain compound conc. time[h] Product product ee (S) 3 Y278 20 mM 9

22% 85%

Examples 4 and 5 Reduction of methyl 3-(2-thiophenyl)-3-oxopropanoateUsing Geotrichum candidum

200 ml of YM medium were inoculated, in a 1-litre Erlenmeyer flask andas the 1st preliminary culture, with the strain Geotrichum candidumATCC34614 and the flasks were incubated at 28° C. for 18 h while beingshaken. As the 2nd preliminary culture, two 1-litre Erlenmeyer flasks,in each case containing 200 ml of GC medium (KH₂PO₄, 11.18 g/l; K₂HPO₄,3.12 g/l; glycerol, 30.0 g/l; yeast extract, 10.0 g/l; polypeptone, 5.0g/l), were in each case inoculated with 10 ml of the 1st preliminaryculture and likewise shaken at 28° C. for 18 h.

As the main culture, a 10 litre fermenter was loaded with 4.6 litres ofGC medium and inoculated with 400 ml of the 2nd preliminary culture. Theculture was grown at 28° C. using an aeration rate of 10 l/min and astirring rate of 800 rpm. After 10 h, the fermenter was harvested. Thecells were sedimented by being centrifuged for 15 min at 6000×g and werethen taken up in 100 mM potassium phosphate buffer (PP buffer), pH 6.4,and stored at 4° C. in a refrigerator.

1.8 g of glucose, 9 ml of 1M PP buffer (pH 7.3) and 71 μl (finalconcentration 20 mM) or 143 μl (final concentration 40 mM) of methyl3-(2-thiophenyl)-3-oxopropanoate were added to 16 g of moist biomass andthe whole was stirred at 28° C. in a 25 ml Schott bottle using amagnetic stirrer. 300 μl of the reaction mixture were removed at regularintervals and extracted with 300 μl of ethyl acetate or toluene and theorganic phase was analysed by gas chromatography. The results wererecorded in Table 3. TABLE 3 Reduction of methyl3-(2-thiophenyl)-3-oxo-propanoate with the strain Geotrichum candidumATCC34614. Starting Reaction Yield of Example compound conc. time [h]Product product ee (S) 4 20 mM 10

71% >98% 5 20 mM 10

72% >98%

Examples 6 to 12 Reduction of Various β-Ketoesters Using Saccharomycescereviseae

A preliminary culture of the strain Saccharomyces cereviseae NG247 wasgrown overnight, at 28° C. and while shaking, in 100 ml of YM medium ina 1-litre Erlenmeyer flask. As the main culture, three 1-litreErlenmeyer flasks, which had each been loaded with 200 ml of YM medium,were in each case inoculated with 10 ml of the preliminary culture andshaken at 28° C. After 6 h, the cultures had reached an optical densityof between 7 and 8 as measured at 600 nm (OD₆₀₀). The cells wereharvested by centrifugation (15 min, 6000×g) and resuspended in 100 mMPP buffer (pH 7)+3% (w/v) glucose as a 10-fold concentrated cellsuspension. 1 M ethanolic solutions of the test substances wereprepared. In the reaction mixtures, the cell suspension was in each casemade to 20 mM with respect to the test substance and incubated at 30° C.while being shaken. 300 μl of the reaction mixture were withdrawn atregular intervals and extracted with 300 μl of ethyl acetate or tolueneand the organic phase was analysed by gas chromatography. The resultsare recorded in Tab. 4. TABLE 4 Enantioselective reduction ofheterocyclic β-ketoesters. Starting Reaction Example Starting compoundcompound conc. time [h] Product Conversion ee 6

20 mM 24 h

92% 98% 7

20 mM 24 h

50% 87% 8

20 mM 24 h

59% 93% 9

20 mM 24 h

92% 81% 10

20 mM 24 h

69% 96% 11

20 mM 24 h

76% 96% 12

20 mM 24 h

99% 99%

Example 13 Preparation of methyl 3-oxo-(2-thiophenyl)propanoate

510 ml of dimethyl carbonate and 1500 ml of toluene were heated to 100°C. in a 2 L flask and a solution of 257 g of 2-acetylthiophene in 510 mlof dimethyl carbonate was then added dropwise within the space of 4hours. The methanol which was formed in the reaction was distilled offas an azeotrope. 120 ml of conc. sulphuric acid were introduced, in 900g of ice, into a 4 L flask and the cooled reaction mixture was addedsuch that 40° C. was not exceeded. The mixture was then stirred and thepH was adjusted to pH 1. The phases were separated and the organic phasewas extracted three times by shaking with an aqueous solution of sodiumsulphate and then concentrated in vacuo. Vacuum distillation of thecrude product yielded 278 g of methyl 3-oxo-(2-thiophenyl)propanoate asa transparent, slightly yellowish liquid (98% pure according to GC, 74%of theory).

Example 14 Preparation ofN-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide

23 g of methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate from experimentsdescribed in the Examples 1 and [lacuna] were initially introduced, and130 ml of a 2-molar methanolic solution of methylamine were added. Thismixture is stirred at 60° C. for 4 h, cooled and then concentrated invacuo. 24 g (purity 87%; 90% of theory) are obtained in this way. Thecrude product can be used as such for the next step or elserecrystallized from methylene chloride and hexane. This yielded 18 g ofN-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (75% of theory) in theform of white crystals.

Example 15 Preparation of (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol

350 ml of dry tetrahydrofuran are initially introduced together with 10g of lithium aluminium hydride and heated to reflux. At the same time, astart is made in adding 17 g ofN-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide from Example 14,dissolved in 150 g of tetrahydrofuran, dropwise. After this dropwiseaddition is complete, the mixture is subsequently stirred overnightunder reflux. The mixture is then cooled down to room temperature and200 ml of water are carefully added dropwise. 135 ml of a 10% solutionof sodium hydroxide were then added dropwise and the solution wasfiltered. The solvent was removed in vacuo. 370 ml of 1 N sodiumhydroxide solution were added to the crude solution and the whole wasextracted 3 times with in each case 370 ml of toluene. The organicphases are combined and the volatile constituents are removed in vacuo,thereby providing 76 g (84% purity, 70% of theory).

Example 16 Purification of (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol

15 g from Example 15 were dissolved in 150 ml of water at boiling heat,after which 5 g of active charcoal were added and the mixture wassubsequently stirred under reflux for a further hour. The suspension wasfiltered in the hot. The filtrate was extracted three times with in eachcase 100 ml of dichloromethane. The combined organic phases wereevaporated and the residue was dissolved, at boiling heat, in 50 ml ofcyclohexane; it was then crystallized, during cooling, using 600 ml ofpetroleum ether. The crystals were filtered, washed with a littlepetroleum ether and dried. This resulted in 12 g of(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol (98% purity, 93% yield).

1. A method for preparing a 3-hydroxy-3-(2-thienyl)propionamide of theformula:heteroaryl-CH(OH)—CH₂—CO—NR²R³ wherein heteroaryl represents2-thiophenyl, which is optionally monosubstituted or polysubstituted byfluorine, chlorine, bromine, nitro, hydroxyl, C₁₋₈-alkyl,C₁₋₄-fluoroalkyl and C₁₋₄-alkoxy; and R² and R³ are each independentlyhydrogen, C₁₋₈-alkyl, C₄₋₁₀-aryl or C₅₋₁₁-arylalkyl; which comprises: a)reducing the compound of the formula:heteroaryl-CO—CH₂—CO—OR¹ wherein heteroaryl is as defined above; and R¹represents hydrogen, C₁₋₈-alkyl, C₄₋₁₀-aryl or C₅₋₁₁-arylalkyl; in thepresence of a microorganism and/or cell preparation; to form theresulting compound of the formula:heteroaryl-CH(OH)—CH₂—CO—OR¹ and then b) reacting said resultingcompound with an amine of the formula:HNR²R³ wherein R² and R³ have the meanings given above.
 2. The methodaccording to claim 1, wherein the microorganism is one selected from thegroup consisting of microorganisms of the genera Saccharomyces,Geotrichum, Candida, Pichia, Hansenula, Yarrowia, Phizopus, Mortierella,Mucor, Sporotrichum, Rhodotorula, Trichoderma, Aspergillus, Penicillium,Pullaria, Cunninghamella and Curvularia.
 3. The method according toclaim 2, wherein the microorganism is Saccharomyces cereviseae.
 4. Themethod according to claim 2, wherein the microorganism is Geotrichumcandidum.
 5. A method for preparing an optically active3-hydroxy-3-(2-thienyl)propionic acid ester compound of the formula:heteroaryl-CH(OH)—CH₂—CO—OR¹ wherein heteroaryl represents 2-thiophenyl,which is optionally monosubstituted or polysubstituted by fluorine,chlorine, bromine, nitro, hydroxyl, C₁₋₈-alkyl, C₁₋₄-fluoroalkyl andC₁₋₄-alkoxy; and R¹ represents hydrogen, C₁₋₈-alkyl, C₄₋₁₀-aryl orC₅₋₁₁-arylalkyl; which comprises reducing the compound of the formula:heteroaryl-CO—CH₂—CO—OR¹ wherein heteroaryl and R¹ are as defined above;in the presence of a microorganism and/or cell preparation.
 6. Themethod according to claim 5, wherein the microorganism is one selectedfrom the group consisting of microorganisms of the genera Saccharomyces,Geotrichum, Candida, Pichia, Hansenula, Yarrowia, Phizopus, Mortierella,Mucor, Sporotrichum, Rhodotorula, Trichoderma, Aspergillus, Penicillium,Pullaria, Cunninghamella and Curvularia.
 7. The method according toclaim 6, wherein the microorganism is Saccharomyces cereviseae.
 8. Themethod according to claim 6, wherein the microorganism is Geotrichumcandidum.